Considerable research suggests that schizophrenia is characterized by a defect in frontotemporal regions with increasing evidence that a defect in the brain white matter of this integrated system is critical to phenomenology. Diffusion tensor imaging (DTI) can be used to quantify the directionality and coherence of water self-diffusion allowing the examination of white matter microstructure in-vivo. Initial DTI studies in schizophrenia demonstrated that white matter pathology is present in chronic patients compared to healthy volunteers, but left major unanswered questions regarding the specificity of anatomic pathology, especially early in the illness and prior to antipsychotic treatment. Moreover, little work to date has been directed at understanding the functional significance of these white matter deficits. Through the K01 mechanism the PI has completed preliminary studies demonstrating lower fractional anisotropy (FA) or higher trace in the middle frontal and superior temporal white matter, cingulum bundle and uncinate fasciculus in first-episode schizophrenia patients compared to healthy volunteers. Larger samples are required to confirm these initial findings, discern their neuropsychological and clinical correlates and to examine how they relate to brain volumetric measures comprising the frontotemporal system. Moreover, recent empirical and theoretical work suggests that a defect in the brain white matter may be a contributing factor to antipsychotic nonresponse in schizophrenia, but research in this area has been limited by the lack of controlled clinical trials from which to recruit patients and test hypotheses. We propose scanning a unique group of 60 antipsychotic drug-naive, first-episode schizophrenia patients to be enrolled in an NIMH- sponsored double-blind 12 week clinical trial of risperidone versus aripiprazole to be conducted under the aegis of our Advanced Center for Intervention and Services Research in Schizophrenia and 60 age- and sex-matched healthy volunteers. The specific aims of this study are to: (1) determine the regional specificity of white matter microstructural pathology in antipsychotic drug-naive first-episode patients with schizophrenia compared to healthy volunteers using DTI; (2) determine the functional correlates of abnormal white matter microstructure in patients compared to healthy volunteers; (3) examine the relationship between frontal lobe white matter microstructure and hippocampal volume in patients compared to healthy volunteers; (4) identify brain white matter regions that predict treatment response in antipsychotic drug-naive patients with first-episode schizophrenia. The identification of these abnormalities at the first episode of illness may be useful for identifying indicators of vulnerability, which may lead to improved early identification of individuals at risk for schizophrenia. [unreadable] [unreadable] [unreadable]